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Background: Common blood markers of arthritis are difficult to interpret in arthritis associated with inflammatory bowel disease (IBD) owing to the coexistence of two inflammatory events. No specific serological disease marker is available for IBD., Objective: To determine a value of serum human cartilage glycoprotein 39 (HC gp39) as a marker of arthritis associated with IBD., Methods: Serum levels of HC gp39 and ultrasensitive C reactive protein (CRP) were determined in 121 patients with IBD: 58 without arthritis (IBD-nonA) and 63 with arthritis (IBD-A), and in 20 healthy controls. IBD was classified as active (aIBD) and non-active (naIBD), and patients with IBD-A were classified as type I, II, and III arthritis by clinical activity indices., Results: HC gp39 was higher in IBD-A than in IBD-nonA (p<0.001) and controls (p<0.01), while no difference was found between IBD-nonA and controls. CRP was increased in both IBD-A and IBD-nonA compared with the controls (p<0.01 and <0.05, respectively) and in aIBD-nonA v naIBD-nonA (p<0.05), but no difference in CRP was found between aIBD-A and naIBD-A. Finally, a correlation was found between the number of affected joints (NAJ) and HC gp39 (r = 0.6, p<0.001)., Discussion: Increased serum levels of HC gp39, which were higher in IBD-A than in IBD-nonA, suggest that this substance might be a marker of arthropathy in IBD. HC gp39, because of its relationship with NAJ in IBD-A, may also be proposed as a disease activity marker in arthritis associated with IBD.

Objectives: Diagnosis in chronic diarrhea in the absence of a distinctive clinical pattern is often challenging, as biochemical tests prescribed at the first evaluation do not show enough sensitivity and specificity to tailor further investigation. Intestinal permeability to sugars is an accurate test for detecting intestinal damage. The aim of this study was to evaluate the diagnostic value of the lactulose/mannitol (L/M) test in patients with chronic diarrhea., Methods: We conducted a prospective cohort study to evaluate the diagnostic value of the L/M test in chronic diarrhea. The test was administered to 261 consecutive patients presenting with three or more bowel movements daily for at least 3 wk. Biochemical tests including complete blood cell count, acute phase reactive proteins, serum albumin and iron, and stool cultures for bacteria, ova, and parasites were assessed at the same time. Additional diagnostic investigations were directed by clinical features as well as first-line test results., Results: Over 3 yr, 120 (46%) of our patients were found to have an organic cause for chronic diarrhea, whereas in 141 (54%) a functional condition was diagnosed. Multivariate logistic regression analysis revealed that the L/M test and C-reactive protein were independent predictors for the final diagnosis of organic cause of chronic diarrhea, with odds ratios of 1.5 (95% CI = 1.29-1.78) and 5.2 (95% CI = 1.90-14.12), respectively. The area under the receiver operating characteristic (ROC) curve of the adjusted model was 0.82, with positive predictive value of 80.4% and negative predictive value of 77.7%., Conclusions: The L/M test is a powerful tool for workup in patients with chronic diarrhea. Introducing the L/M test as first-level test effectively improves the selection of patients who need further evaluation.

The effect of oral zinc (Zn) treatment was studied in the liver, kidneys and intestine of Long-Evans Cinnamon (LEC) rats in relation to metals interaction and concentration of metallothionein (MT) and glutathione (GSH). We also investigated the change in the activity of antioxidant enzymes and determined the biochemical profile in the blood and metal levels in urine. We showed that the Zn-treated group had higher levels of MT in the hepatic and intestinal cells compared to both untreated and basal groups. Tissue Zn concentrations were significantly higher in the Zn-treated group compared to those untreated and basal, whereas Cu and Fe concentrations decreased. The antioxidant enzyme activities in the Zn-treated group did not change significantly with respect to those in the basal group, except for hepatic glutathione peroxidase activity. Moreover, the biochemical data in the blood of Zn-treated group clearly ascertain no liver damage. These observations suggest an important role for Zn in relation not only to its ability to compete with other metals at the level of absorption in the gastrointestinal tract producing a decrease in the hepatic and renal Cu and Fe deposits, but also to MT induction as free radical scavenger.

The Long-Evans Cinnamon (LEC) rat is a mutant animal model for Wilson's disease. It is known that an abnormal accumulation of Cu and Fe in the liver and low concentrations of both ceruloplasmin and Cu in the serum occur in these rats. The accumulation of Cu is explained by the defective expression of the Cu-transporting P-type ATPase gene, homologous to the gene for Wilson's disease (ATP7B). The aim of this work was to clarify the action mechanism of Zn, and to verify the role that this metal plays in LEC rats in short-term treatment experiments (1 and 2 weeks) on concentrations of Cu, Zn, Fe, metallothionein (MT), 8-hydroxy-2'-deoxyguanosine (oh(8)dG) and on the activity of antioxidant enzymes. It is well known that Zn induces MT and has the ability to prevent redox-active metals, Cu and Fe, binding to and causing oxidative damage at active sites of Zn metalloenzymes and nonspecific binding sites on proteins. Zn administration reduces Cu and Fe transport from mucosal to serosal intestinal sides through competitive mechanisms. Our findings show that treatment with zinc acetate increases tissue Zn and MT contents and decreases Cu and Fe concentrations in the liver and kidneys, even if hepatic Zn and MT concentrations decrease with treatment period. Induction of MT synthesis by Zn contributes to the reduction in free radicals produced by Cu and Fe. We also observed that the superoxide dismutase (SOD)activity in liver decreases with treatment duration in association with the Cu and Fe liver decrease. However, the SOD activity in kidney increases in untreated rats at 2 weeks relative to those untreated for 1 week.

The effect of oral Zn treatment was studied in the liver and kidneys of 26 male Long-Evans Cinnamon (LEC) rats (mutant animals, 5 weeks old) in relation to both the interaction between Zn and Cu and the localisation and concentration of metallothionein (MT). Rats receiving 80 mg zinc acetate daily by gavage and control rats receiving no treatment were killed after 1 or 2 weeks. By immunohistochemical and analytical chemical techniques we revealed that treated rats had higher levels of MT in the hepatic and renal cells compared to untreated ones. Tissue Zn concentrations were significantly higher in treated rats compared to untreated whereas Cu concentrations decreased in the liver and kidneys as indicated by analytical chemical analyses. MT levels also decreased with treatment period. A histochemical procedure, obtained using autofluorescence of Cu-metallothioneins, confirms these findings: after 2 weeks, the signal decreased in both the liver and kidney sections. This gives a greater understanding of the mechanism of Cu metabolism in the two tissues considered. These results suggest that Zn acts both to compete for absorption on the luminal side of the intestinal epithelium and to induce the synthesis of MT.

Patients with Crohn's disease (CD) are at higher risk of hepatitis C (HCV) and B virus (HBV) infection, because of surgical and/or endoscopic procedures. However, the prevalence of HCV and HBV infection in CD is unknown. This issue may be relevant because of the growing use of immunomodulatory drugs in CD. The purpose of this study was to assess, in a multicenter study, the prevalence and risk factors of HCV and HBV infection in CD. The effect of immunomodulatory drugs for CD on the clinical course of hepatitis virus infections and of interferon-alpha (IFN-alpha) on the course of CD was examined in a small number of patients. Sera from 332 patients with CD and 374 control subjects (C) were tested for the following: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), HBcAb, HBeAg, HBeAb, anti-HCV, and HCV-RNA. An additional 162 patients with ulcerative colitis (UC) were tested as a disease control group. Risk factors were assessed by multivariate statistical analysis. Infection by either HCV or HBV was detected in 24.7% of patients with CD. In the age groups younger than 50 years, HCV prevalence was higher in CD than in C (p = 0.01). HCV infection in CD was associated with surgery (OR 1.71; 95% CI 1.00-2.93; p = 0.04), blood transfusions (OR 3.39; 95% CI 1.04-11.04; p = 0.04), and age (OR 2.3; 95% CI 1.61-3.56; p < 0.001). The event CD-related surgery appeared to be the main risk factor for HCV infection in CD. HCV prevalence was higher in CD (7.4%) than in UC (0.6%) (p = 0.001). HBcAb positivity was higher in CD (10.9%) and UC (11.5%) than in C (5.1%) (CD vs. C: p = 0.016; UC vs. C: p = 0.02), associated with age (OR 2.08; 95% CI 1.37-3.17; p = 0.001) and female gender (OR 2.68; 95% CI 1.37-3.17; p = 0.001) in CD and to UC duration (OR 1.20; 95% CI 1.06-1.36; p = 0.002). Immunomodulatory drugs did not influence the course of HBV or HCV infection in seven patients with CD, and IFN-alpha for chronic hepatitis C did not affect CD activity in six patients with CD. It is concluded that HBV prevalence is higher in CD than in C at all ages, whereas HCV prevalence is increased in young patients with CD, because of a greater need for surgery. The higher HCV (but not HBV) prevalence in CD than in UC suggests that the host immune response may influence the risk of HCV infection. Although a relatively high proportion of patients with CD showed HBV and/or HCV infections, this should not influence treatment strategies for CD.

Objectives: Intestinal inflammation is associated with enteric nervous system alterations, at both inflamed and noninflamed sites. The perception of stimuli from the GI tract is enhanced during inflammatory conditions, but it is unknown whether visceral hypersensitivity is limited to the inflamed area or diffuse throughout the entire GI tract. Moreover, although stress can reactivate inflammatory processes in the gut, it is unknown if this can alter perception from the GI tract. Our aim was to determine if patients with ulcerative colitis (UC) have increased esophageal sensitivity to distention and whether this is modified by experimental stress., Methods: Ten UC patients and 12 healthy volunteers (HVs) underwent gradual balloon distension of the esophagus to assess their visceral sensitivity. Perceptive and pain thresholds were evaluated in basal conditions and after induction of experimental stress (cold water pressure test) while blood pressure and heart rate were monitored., Results: Patients with UC had perceptive thresholds to distension similar to HVs (14.8+/-2.0 ml of air vs 14.5+/-3.0 ml); in contrast, the volume increment needed to evoke pain was significantly lower in UC patients than in HVs (58.9% vs 149.9%, p < 0.05). Physical stress caused a similar decrease in perceptive thresholds in HVs (-29.1+/-8.4%) and patients (-17.7+/-9.1%), but pain thresholds were significantly decreased only in HVs (-28.3+/-7.1% vs -11.5+/-12.3%)., Conclusions: UC is characterized by increased esophageal sensitivity, indicating the existence of diffuse hyperalgesia during intestinal inflammatory processes. This increased sensitivity may account for the frequent upper GI symptoms these patients complain of when in clinical remission.

Objectives: Small intestinal permeability is often increased in patients with Crohn's disease and may be pathogenic for clinical relapses. No effective prophylactic treatment is available for these patients. The aim of this study was to ascertain whether zinc supplementation may improve intestinal permeability., Methods: We studied 12 patients with quiescent Crohn's disease who had been in remission for at least 3 months and had increased intestinal permeability on two separate occasions within the last 2 months. Patients received oral zinc sulfate supplements (110 mg three times a day) for 8 weeks and were followed-up for 12 months thereafter to monitor relapses., Results: We found that the lactulose/mannitol ratio was significantly higher before supplementation than after (0.041 +/- 0.003 versus 0.026 +/- 0.005). During follow-up, 10 patients had normal intestinal permeability and did not relapse; of the remaining two who had increased intestinal permeability, one relapsed., Conclusions: Our findings show that zinc supplementation can resolve permeability alterations in patients with Crohn's disease in remission. Improving intestinal barrier function may contribute to reduce the risk of relapse in Crohn's disease.

Background and Aim: Zinc enhances cell protection against infection and injury and the healing processes themselves. We evaluated the effect of zinc supplementation at different doses on a model of experimental colitis in the rat., Methods: Colitis, induced by intra-rectal instillation of dinitrobenzen-sulphonic acid, was assessed at 1 week by examining: general outcome and macroscopic damage, myeloperoxidase activity, mucosal zinc, iron and metallothionein concentrations. Rats received zinc sulphate, 2 mg/kg or 30 mg/kg, twice a day by gavage for 9 days, starting 3 days before the induction of colitis, or intrarectal instillation of zinc (20 mg/kg) once daily starting 8 hours after the induction of colitis and for 6 days thereafter, Results: Zinc-treated rats had less diarrhoea, higher body weight and lower colonic weight than untreated rats but no effect was observed on macroscopic inflammation, adhesions, colonic distension and neutrophil infiltration of the colonic mucosa. Zinc supplementation did not affect mucosal iron and zinc concentrations or plasma zinc levels in colitic rats. Metallothionein synthesis was induced in control rats and to a lesser extent in colitic rats., Conclusion: Zinc administration induces metallothionein synthesis but has little effect on the short-term course of experimental colitis.

Exercise may promote a healthy life, improving functional capacities. Little is known about the effects of physical activity in inflammatory bowel disease. Altered immunity is implicated in the pathogenesis of inflammatory bowel diseases. An acute, albeit transient acute immune response, follows heavy endurance exercise. Epidemiological data support the role of physical activity in lowering the risk of inflammatory bowel disease. Moderate physical exercise (60% VO2max) does not cause significant changes in symptoms, intestinal transit time, and permeability. Neutrophil function appears to be primed at basal conditions with significant activation after exercise. At present, mild exercise can be recommended to patients with quiescent inflammatory bowel disease as well as other chronic diseases such as rheumatoid arthritis, while caution is still needed for active disease patients. Patients with inflammatory bowel disease show a reduced exercise capacity after surgery, especially after extensive resections.

Background: Physical exercise may exacerbate the disturbed homeostasis of Crohn's disease patients., Aim: To examine the effect of moderate physical exercise on gastrointestinal function in a group of Crohn's disease patients in remission., Patients and Methods: The effect of one-hour's exercise at a maximum of 60% oxygen consumption was evaluated in six males with ileal Crohn's disease in remission on orocaecal transit time (breath test to lactulose), intestinal permeability (6-hours' urinary excretion of a sugar mixture of lactulose/mannitol), polymorphonuclear leucocytes function (peripheral blood chemiluminescence), lipoperoxidation (plasma malondialdehyde) and antioxidant trace elements (urinary and plasma zinc and copper concentrations). Six healthy age-matched subjects served as controls., Results: Exercise did not elicit subjective symptoms or changes in intestinal permeability and lipoperoxidation. Orocaecal transit time increased after exercise in Crohn's disease patients (72 min +/- 30 vs 100 min +/- 34) with no significant difference from controls (77 min +/- 20 vs 83 min +/- 23). Neutrophils, primed pre-exercise in Crohn's disease patients showed an increased post-exercise chemiluminescence similar to controls. Zinc urinary output significantly increased after exercise in Crohn's disease patients and remained unchanged in control subjects., Conclusions: Moderate aerobic exercise has no significant effect on the gastrointestinal parameters examined. However, basal neutrophil activation and exercise in Crohn's disease patients may trigger an excessive production of oxygen metabolites. Moreover, exercise may contribute to an increased risk of zinc deficiency.

Objective: Wilson's disease is effectively treated by zinc administration which, in vitro, increases metallothionein concentrations. To ascertain whether the latter also occurs in humans we measured metallothionein and trace element concentrations in the duodenal mucosa of 15 Wilson's disease patients: 12 treated with zinc sulphate, two treated with penicillamine, and one not yet on treatment. The control group consisted of 17 patients with dyspepsia, who underwent the same study protocol., Methods: Metallothionein and trace element concentrations were measured in duodenal mucosa biopsies according to the silver-saturation hemolysate method and atomic absorption spectrophotometry., Results: Metallothionein concentrations increased by 1500% after zinc and 150% after penicillamine in Wilson's disease patients, with respect to controls who had negative endoscopy and Wilson's disease patients who were not treated. A significant correlation was found between metallothionein and duodenal zinc concentrations. Mucosal iron concentration increased in Wilson's disease patients whether they were treated with zinc or penicillamine. Duodenum with duodenitis also had significantly increased iron levels compared with normal duodenum., Conclusions: Zinc administration increases intestinal metallothionein in Wilson's disease patients. The blockade of copper absorption and its elimination in the stools on desquamation of the intestinal cells probably explains one of the mechanisms underlying the effect of zinc treatment. Despite normal endoscopy, Wilson's disease patients present increased mucosal iron concentrations similar to those in controls with duodenitis. Metallothionein may therefore prevent oxidative damage caused by metal toxicity.

Background: Different exogenous factors are believed to play a role in the pathogenesis of ulcerative colitis. Smoking habits and other risk factors have received much attention. It has recently been reported that appendectomy decreases the risk of ulcerative colitis., Aim: Aim of the study was to further examine the role of appendectomy in ulcerative colitis., Methods: A large multicentre case control study was performed. Cases were all patients with a recent new diagnosis of ulcerative colitis (from 1990 to 1994) at participating centres. One or two controls attending the orthopaedic and surgical units were considered and matched to cases for age (+/- 5 years), sex and year of diagnosis. A total of 536 cases and 755 controls were enrolled. Mean age of cases was 37.9 years (range 2-92). Assessment of exposure was done by examining the clinical records and by interview, if necessary. Smoking habits, alcohol consumption, use of oral contraceptives, type of occupation and area of residence were also recorded. Odds ratio and 95% confidence intervals were calculated by conditional logistic regression analysis., Results: Forty-one out of the 536 cases (7.6%) and 150 out of the 755 controls (19.9%) had been submitted to appendectomy. A total of 110 out of 536 cases (20.5%) and 135 out of 753 (17.9%) controls had had tonsillectomy. Seven out of 41 cases and 15 out of 755 controls underwent appendectomy for recurrent pain. In all ulcerative colitis patients, appendectomy had been performed before the onset of disease. When data were adjusted for the confounding variables, ulcerative colitis patients were less likely to have had appendectomy compared with controls (odds ratio = 0.3, confidence interval = 0.19-0.48). There was no significant association of ulcerative colitis with tonsillectomy (odds ratio = 1.09, confidence interval = 0.76-1.58). The well recognized inverse association of ulcerative colitis with cigarette smoking was also shown in this study., Conclusions: The present data emerging from a large multicentre study, confirm that appendectomy has a protective role for the development of ulcerative colitis.

Gut motility disorders and altered pain perception were reported in patients with irritable bowel syndrome (IBS). To verify foregut involvement in IBS, we studied 30 patients using esophageal manometry and 24-hr pH monitoring of the distal esophagus. Two subgroups of patients underwent esophageal provocative tests (bethanechol 50 micrograms/kg subcutaneously and esophageal balloon distension test). Twelve healthy volunteers formed a control group. A pain threshold on esophageal distension significantly lower than in healthy subjects (11.5 +/- 1 ml vs 22.2 +/- 1.7 ml, P < 0.01) was found in IBS patients. On the other hand, no differences between patients and controls were detected in lower esophageal sphincter pressure and length, esophageal body motility, or GER pattern; furthermore, bethanechol stimulation elicited similar esophageal body motility changes. Our study could confirm no detectable basal or bethanechol-induced esophageal motility disorders in IBS patients, nor enhanced GER. Esophageal involvement in IBS consists of a lower pain threshold on esophageal distension, possibly reflecting an altered visceral receptor sensitivity or modulation throughout the gut.

Patients with chronic liver disease may have taste impairment and altered zinc metabolism. We evaluated Taste Detection Thresholds (TDTs) in 60 patients with liver cirrhosis and correlated the findings with disease severity and alcoholic etiology. Plasma zinc levels and urinary output were also measured. A placebo-controlled treatment trial with zinc sulphate was made in 15 patients with compensated cirrhosis in order to ascertain whether zinc deficiency caused taste alterations. Taste detection of salty, sweet and acid tastants was significantly impaired in all cirrhotic patients in comparison with normal subjects. TDTs were not influenced either by the etiology or the severity of the disease. All groups of patients had low plasma zinc levels and decompensated cirrhosis had a significantly increased urinary output of zinc. No correlation was found between taste acuity and plasma zinc levels when only cirrhotic patients were considered. The effect of zinc supplementation on TDTs did not appear to be inferior to that of the placebo. Our results indicate that taste impairment in cirrhotics is due to the disease process per se and not to zinc deficiency.